Electrophysiologic features of SYT2 mutations causing a treatable neuromuscular syndrome

Abstract

Objectives: To describe the clinical and electrophysiologic features of synaptotagmin II (SYT2) mutations, a novel neuromuscular syndrome characterized by foot deformities and fatigable ocular and lower limb weakness, and the response to modulators of acetylcholine release. Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders caused by abnormal signal transmission between motor axons and skeletal muscle. Methods:1 Mutations in an increasing number of presynaptic proteins, components of the synaptic basal lamina, proteins involved in endplate development and maintenance, and more recently in protein glycosylation 2 have been reported, causing novel and complex phenotypes. Since most CMS are treatable, diagnosing them is of utmost importance.Signal transmission at the neuromuscular junction is mediated via the release of acetylcholine from synaptic vesicles.3 This process is rendered calcium sensitive by members of the synaptotagmin protein family, which also have a role in vesicle priming and in reducing spontaneous transmitter release.4,5 Synaptotagmin II (SYT2) is the major isoform expressed at the neuromuscular junction, and Syt2 knockout mice show markedly reduced calcium-evoked transmitter release.6 Synaptotagmins interact with SNAP-25, 5 and mutations in SNAP25B have been described in patients with myasthenia and additional CNS phenotypes. Herein, we describe the clinical and electrophysiologic characteristics of 2 multigenerational families displaying a novel human motor syndrome caused by dominant SYT2 mutations: c.920T.G

The Increasing Genetic and Phenotypical Diversity of Congenital Myasthenic Syndromes

“…In CMS subtypes in which the primary defect results in impairment of ACh release, RNS performed at high frequency for a prolonged period (e.g., 10Hz for 5 minutes) results in an opposing effect and an increment in CMAP amplitude is observed. [24][25][26] This is similar to the effect seen in the immune-mediated Lambert-Eaton myasthenic syndrome (LEMS). 27 In other presynaptic CMS subtypes in which the defect is not in impairment of ACh release, but in its synthesis in the presynaptic nerve terminal (e.g., CHAT-CMS), often no decrement is detected at low-frequency (3 Hz) RNS, and it is not until the pool of synaptic vesicles has been exhausted that any decrement is observed.…”

Congenital myasthenic syndrome with mild intellectual disability caused by a recurrent SLC25A1 variant

“…Lambert Eaton Myasthenic Syndrome (LEMS) is caused by antibodies against the presynaptic voltage gated calcium channel. Another CMS phenotype overlapping with LEMS, which results in impaired presynaptic calcium signalling, has been described recently [17]. This includes increment on RNS after a period of maximum voluntary contraction, and response to 3,4-diaminopyridine (3,4-DAP), a presynaptic potassium channel blocker.…”

Vesicular acetylcholine transporter defect underlies devastating congenital myasthenia syndrome

“…9 SYT2 encodes synaptotagmin II, involved in calcium-evoked vesicular transmitter release, and heterozygotes for SYT2 mutations have even milder motor symptoms with no CNS manifestations. 8 Hypoglycosylation of synapsespecific proteins due to recessive mutations in DPAGT1 11 and GFPT1 10 can functionally impair both central and motor synapses and CNS symptoms were observed even in cases with relatively mild motor deficits. This is likely explained by the wider implications of glycosylation defects.…”

“…Presynaptic defects can affect the synthesis and release of acetylcholine from nerve terminals. 1,5,6 Several genes were reported to underlie presynaptic CMS, including CHAT, encoding choline acetyltransferase, which is critical for the synthesis of acetylcholine in neurons; MUNC13, 7 SYT2, 8 and SNAP25B, 9 which are required for priming the synaptic vesicles for exocytosis and calcium-evoked transmitter release; and GFPT1 10 and DPAGT1, 11 which glycosylate nascent peptides. In this report, we describe a devastating CMS due to a defect in a different presynaptic protein and the underlying genetics.…”